Hydrogel filaments for biomedical uses

This application claims the benefit of U.S. provisional patent application No. 61/016,342, filed Dec. 21, 2007, the entire disclosure of which is incorporated herein by reference.

The present invention relates generally to medical treatment apparatus and methods, more particularly, hydrogel filaments visible under x-ray fluoroscopy and magnetic resonance, and methods for use of such materials in biomedical treatment.

Presently, for patients suffering from cerebral and/or peripheral vascular disease, an interventional neuroradiologist/neurosurgeon has three main embolic device choices: platinum coils, hydrogel/platinum coils, or degradable polymer/platinum coils. All three types of coils are deployed into aneurysms and have advantages and disadvantages associated with them. Platinum coils are easy to deploy through standard microcatheters, are available in wide ranges of softness, and are best suited for aneurysms with small sizes or necks. Hydrogel/platinum coils are also easy to deploy through standard microcatheters. Although hydrogel/platinum coils are relatively stiffer than platinum coils and can be challenging to deploy inside aneurysms, they give acceptable results in a broader range of sac and neck sizes. Degradable polymer/platinum coils are easily tracked and deployed into aneurysm sacs; however, they only give acceptable results in aneurysms with small sizes or necks.

Despite the three coil varieties, there exists an unmet clinical need for embolic devices that deploy easily into aneurysm sacs (like platinum coils) and result in durable occlusion in a wide variety of aneurysm sizes (like hydrogel/platinum coils). Among the benefits of the apparatus and methods of the present description is a device that tracks through a microcatheter with less friction than a platinum coil, deploys in the aneurysm sac like the softest platinum coil on the market, expands like the hydrogel/platinum coils, and provides durable occlusion of the aneurysm sac, while permitting the interventional neuroradiologist/neurosurgeon, or surgeon, to use standard microcatheters and other associated equipment.

The improved durability of hydrogel/platinum coils is believed to be a result of the increased volumetric filling of the aneurysm sac and the resulting increase in stability of the coil mass. A current version of the hydrogel/platinum coil has an overcoil which limits the expansion of the hydrogel. In preclinical models, while current overcoiled hydrogel/platinum coils provide better results than platinum coils, it is believed that a non-overcoiled hydrogel device would be less stiff than current overcoiled versions. The present description provides an embolic device that is capable of providing increased volumetric filling, more so than both platinum coils and overcoiled hydrogel/platinum coils, with less stiffness than overcoiled hydrogel/platinum coils.

In large and giant aneurysms, inflammatory complications can occur, presumably due to the large amount of thrombus formation and organization. It is believed that with the increased volumetric filling of the aneurysm sac provided by the hydrogel, decreased thrombus formation and organization occurs and presumably fewer inflammatory complications result. The present description provides an embolic device which could reduce inflammatory complications.

An uncommon, but potentially dangerous, complication occurs when a coil gets interlocked within the winds of the coil itself. In this case, one can neither push nor pull the coil while keeping the device intact within the aneurysm site. The only option is to pull back and unwind the coil from the aneurysm site to the groin. The potentially dangerous result is a stretched coil. Although stretch resistant coils have been developed, this complication has not been eliminated, and still poses a dangerous threat to a patient. It is believed that the device of the present description eliminates this complication altogether.

Described herein are apparatuses, compositions, systems and associated methods to occlude structures and malformations in body lumens with hydrogel filaments with delayed controlled rates of expansion including one or more visualization agents permitting the repositioning of the device once inside the structure or malformation. The structures and malformations can be a result of any number of cerebral and/or peripheral diseases. Generally, the controlled rate of expansion is imparted through the incorporation of ethylenically unsaturated monomers with ionizable functional groups, (e.g. amines, carboxylic acids). For example, if acrylic acid is incorporated into the cross-linked polymeric network, the hydrogel is then incubated in a low pH solution to protonate the carboxylic acids. After the excess low pH solution has been rinsed away and the hydrogel dried, the hydrogel can be introduced through a microcatheter filled with blood or saline at physiological pH. The hydrogel cannot and will not expand until the carboxylic acid groups deprotonate. Conversely, if an amine-containing monomer is incorporated into the cross-linked network, the hydrogel is incubated in a high pH solution to deprotonate amines. After the excess high pH solution has been rinsed away and the hydrogel dried, the hydrogel can be introduced through a microcatheter filled with blood or saline at physiological pH. The hydrogel cannot and will not expand until the amine groups protonate.

In one embodiment described herein is a device for implantation comprising a difunctional, low molecular weight ethylenically unsaturated shapeable macromer; an ethylenically unsaturated monomer; and a visualization agent, wherein the device contains no support members. In one embodiment, the support members are metallic.

In one embodiment, the macromer has a molecular weight of about 100 grams/mole to about 5000 grams/mole. In another embodiment, the hydrogel is environmentally-responsive. In yet another embodiment, the ethylenically unsaturated monomer comprises one or more ionizable functional groups.

In one embodiment, the macromer comprises polyethylene glycol, propylene glycol, poly(tetramethylene oxide), poly(ethylene glycol) diacrylamide, poly(ethylene glycol) diacrylate, poly(ethylene glycol) dimethacrylate, derivatives thereof, or combinations thereof. In another embodiment, the ethylenically unsaturated monomer comprises N,N′-methylenebisacrylamide, N-vinyl pyrrolidinone, 2-hydroxyethyl methacrylate, derivatives thereof, or combinations thereof.

In one embodiment, the visualization agents include radiopaque elements comprising an aromatic ring having a single unsaturation point and at least one iodine atom, tantalum, barium, salts thereof, or combinations thereof. In one embodiment, the visualization agent an aromatic ring having a single unsaturation point and two iodine atoms. In one embodiment, the visualization agent comprises gadolinium or iron oxide to impart visibility under magnetic resonance imaging.

In one embodiment, the ethylenically unsaturated monomer and the visualization agent comprise 2,4,6-triiodophenyl penta-4-enoate, 5-acrylamido-2,4,6-triiodo-n,n′-bis-(2,3 dihydroxypropyl) isophthalamide, derivatives thereof, or combinations thereof.

In one embodiment, the polymerization of the macromer and the monomer is initiated by N,N,N′,N′-tetramethylethylenediamine, ammonium persulfate, azobisisobutyronitrile, benzoyl peroxides, 2,2′-azobis(2-methylpropionamidine) dihydrochloride, derivatives thereof, or combinations thereof.

In one embodiment, the ionizable functional groups comprise acidic groups or basic groups. In one embodiment, the basic group comprises amine groups, derivatives thereof, or combinations thereof. In another embodiment, the acidic groups comprise a carboxylic acid, derivatives thereof, or combinations thereof.

In one embodiment, the hydrogel is substantially free of acrylamide. In another embodiment, the hydrogel is substantially non-bioresorbable. In another embodiment, the hydrogel is bioresorbable.

One embodiment described herein is a method for preparing a device for implantation in an animal comprising: a) combining a difunctional, low molecular weight ethylenically unsaturated shapeable macromer; an ethylenically unsaturated monomer; a visualization agent, and a solvent to prepare a prepolymer solution; and b) treating the prepolymer solution to prepare a hydrogel that is expansible at physiological conditions.